Drug discovery and optimization constitutes one of the most important targets in medicinal chemistry. Because of their wide bioactivity spectra, nitrogen-containing heterocycles have received significant attention in many bio(organic) studies. The current review is a simple summary of different environmentally benign synthetic procedures that afford a variety of quinazoline and quinazolinone scaffolds with promising biological potential. The molecular modeling of various classes has also been discussed to elucidate the molecular reasons that led to the observed inhibition profile of different protein kinases, including which amino acids in their active sites would be involved in the anticipated bonding interactions. Furthermore, this article aims to investigate which classes deserve further development to get more specific and more potent quinazoline and quinazolinone candidates in various biological targets.